The first generation of CAR-T cancer treatments, Novartis’ Kymriah and Gilead’s Yescarta, are personalized cell therapies that target CD19, a biomarker on B cells implicated in some blood cancers. Although the products have greatly improved the prognoses for patients with leukemia and lymphoma, as many as one-third of patients eventually relapse.
Now, scientists at City of Hope are developing a new CAR-T treatment that they believe could be used to treat patients who have relapsed after receiving CD19-targeted cell therapies. Their CAR-T therapy homes in on a different target: B cell-activating factor receptor (BAFF-R). The treatment eradicated CD19-resistant leukemia and lymphoma cells in animal models, they reported in Science Translational Medicine.
BAFF-R was selected as the target because “is almost ubiquitously expressed in all subtypes of lymphomas and leukemias and is critical for survival of the tumor cell,” said lead author Larry Kwak, M.D., Ph.D., vice president and deputy director of City of Hope’s comprehensive cancer center, in an interview with FierceBiotechResearch.
“That’s really important because the reason we’re getting the problem of treatment failures with the CAR-T cells is that CD19 is not absolutely required for survival of the tumor cell. That means the tumor cell can simply reduce its expression or eliminate the expression altogether of that protein and escape the therapy,” Kwak added.
City of Hope is now planning a clinical trial of its BAFF-R CAR-T treatment in leukemia and lymphoma patients who relapsed after receiving approved CD19-targeted therapies. The trial will open for enrollment next year. City of Hope has licensed the BAFF-R CAR-T technology to Irvine, CA-based Pepromene Bio.
Kwak’s team tested the BAFF-R-aimed cell therapy in animals with several types of CD19-therapy-resistant tumors. They observed tumor shrinkage and prolonged survival, particularly in models of Burkitt lymphoma. Those animals achieved 100% long-term survival, the researchers reported.
Then they compared CD19-targeted cells with their CAR-T treatment in animals with a mix of tumors that were CD19-positive and negative. The BAFF-R CAR-T cells were active against both tumor types, they reported, while the CD19 cells were not.
Similar results were seen in tumor samples taken from patients who relapsed after being treated with Amgen’s Blincyto, a drug for acute lymphoblastic leukemia (ALL) that also targets CD19. When the City of Hope team compared FDA-approved CAR-T cells with their BAFF-R treatment, they found that the BAFF-R cells were more consistently active against Blincyto-resistant tumors.
Finding solutions to immunotherapy resistance is a major priority in the oncology community. Scientists at the University of Pennsylvania, where CAR-T was pioneered, are looking at the problem of T cell “exhaustion,” which can cause relapses. In June, a Penn team reported the discovery of a protein called TOX that they believe could be targeted to reverse T cell exhaustion.
Scientists at the La Jolla Institute for Immunology are investigating the role of proteins called Nr4a transcription factors in T cell exhaustion. They found that inhibiting three Nr4a transcription factors could improve the potency of CAR-T cells.
Like existing CAR-T therapies, City of Hope’s BAFF-R treatment will involve collecting T cells from patients, engineering them to recognize the molecular marker and then re-administering them. City of Hope plans to manufacture the cells at its own Cellular Therapy Production Center. It plans to recruit 30 patients with ALL who relapsed after being treated with Blincyto, Kymriah or Yescarta.
Kwak believes the BAFF-R-directed CAR-T could eventually prove promising even earlier in the treatment of leukemia and lymphoma. “Because of it’s superiority to CD19 in the head-to-head animal experiments, we’re confident we’ll eventually bring this up for clinical testing in the front line.”